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The Histone Methyltransferase Mixed Lineage Leukemia (MLL) 3 May Play a Potential Role on Clinical Dilated
Ding-Sheng Jiang1,2,3, Xin Yi4,5,6, Rui Li1
1Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Insights
Histone methyltransferase MLL3 is elevated in dilated cardiomyopathy (DCM), potentially driving disease progression by altering histone marks and key protein levels. This finding offers new insights into DCM pathogenesis.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Molecular Medicine
Background:
- Histone modifications are crucial in dilated cardiomyopathy (DCM) pathogenesis.
- The specific roles of histone methyltransferases (HMTs), particularly the mixed lineage leukemia (MLL) family, in DCM remain largely unknown.
Purpose of the Study:
- To investigate the expression patterns and functional significance of MLL family members in DCM.
- To explore the relationship between MLL3 expression and cardiac remodeling markers in DCM.
Main Methods:
- Analysis of MLL family gene and protein expression in human DCM and normal heart samples.
- Induction of cardiac remodeling in a mouse model using transverse aortic constriction (TAC).
- Quantitative real-time PCR and Western blotting to assess gene and protein expression levels.
Main Results:
- MLL3 mRNA and protein levels were significantly increased in DCM hearts and TAC-induced mouse hearts.
- MLL3 expression correlated with left ventricular end-systolic diameter and ejection fraction.
- Elevated levels of di-methylated histone H3 lysine 4 (H3K4me2) and specific regulatory proteins (Smad3, GATA4, EGR1) were observed in DCM hearts.
Conclusions:
- MLL3 plays a potential role in the pathological processes of DCM.
- MLL3 may exert its effects by regulating H3K4me2 levels and the expression of Smad3, GATA4, and EGR1.
- These findings highlight MLL3 as a potential therapeutic target for DCM.
Abstract:
Histone modifications play a critical role in the pathological processes of dilated cardiomyopathy (DCM). While the role and expression pattern of histone methyltransferases (HMTs), especially mixed lineage leukemia (MLL) families on DCM are unclear. To this end, twelve normal and fifteen DCM heart samples were included in the present study. A murine cardiac remodelling model was induced by transverse aortic constriction (TAC). Real-time PCR was performed to detect the expression levels of MLL families in the mouse and human left ventricles. The mRNA level of MLL3 was significantly increased in the mouse hearts treated by TAC surgery. Compared with normal hearts, higher mRNA and protein level of MLL3 was detected in the DCM hearts, and its expression level was closely associated with left ventricular end systolic diameter (LVEDD) and left ventricular ejection fraction (LVEF). However, the expression level of other MLL families (MLL, MLL2, MLL4, MLL5, SETD1A, and SETD1B) had no obvious change between control and DCM hearts or remodeled mouse hearts. Furthermore, the di-methylated histone H3 lysine 4 (H3K4me2) but not H3K4me3 was significantly increased in the DCM hearts. The protein levels of Smad3, GATA4, EGR1, which might regulate by MLL3, were remarkably elevated in the DCM hearts. Our hitherto unrecognized findings indicate that MLL3 has a potential role on pathological processes of DCM via regulating H3K4me2 and the expression of Smad3, GATA4, and EGR1.
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